The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition.

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  • Author(s): Schick C;Schick C; Brömme D; Bartuski AJ; Uemura Y; Schechter NM; Silverman GA
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1998 Nov 10; Vol. 95 (23), pp. 13465-70.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Antigens, Neoplasm/*chemistry ; Serine Proteinase Inhibitors/*chemistry ; Serpins/*chemistry; Amino Acid Sequence ; Animals ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Binding Sites ; Escherichia coli ; Humans ; Molecular Sequence Data ; Serine Endopeptidases/metabolism ; Serine Proteinase Inhibitors/genetics ; Serine Proteinase Inhibitors/metabolism ; Serpins/genetics ; Serpins/metabolism ; Structure-Activity Relationship
    • Abstract:
      The high-molecular-weight serine proteinase inhibitors (serpins) are restricted, generally, to inhibiting proteinases of the serine mechanistic class. However, the viral serpin, cytokine response modifier A, and the human serpins, antichymotrypsin and squamous cell carcinoma antigen 1 (SCCA1), inhibit different members of the cysteine proteinase class. Although serpins employ a mobile reactive site loop (RSL) to bait and trap their target serine proteinases, the mechanism by which they inactivate cysteine proteinases is unknown. Our previous studies suggest that SCCA1 inhibits papain-like cysteine proteinases in a manner similar to that observed for serpin-serine proteinase interactions. However, we could not preclude the possibility of an inhibitory mechanism that did not require the serpin RSL. To test this possibility, we employed site-directed mutagenesis to alter the different residues within the RSL. Mutations to either the hinge or the variable region of the RSL abolished inhibitory activity. Moreover, RSL swaps between SCCA1 and the nearly identical serpin, SCCA2 (an inhibitor of chymotrypsin-like serine proteinases), reversed their target specificities. Thus, there were no unique motifs within the framework of SCCA1 that independently accounted for cysteine proteinase inhibitory activity. Collectively, these data suggested that the sequence and mobility of the RSL of SCCA1 are essential for cysteine proteinase inhibition and that serpins are likely to utilize a common RSL-dependent mechanism to inhibit both serine and cysteine proteinases.
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    • Grant Information:
      F32 CA073031 United States CA NCI NIH HHS; CA69331 United States CA NCI NIH HHS; CA73031 United States CA NCI NIH HHS; HD28475 United States HD NICHD NIH HHS
    • Accession Number:
      0 (Antigens, Neoplasm)
      0 (Serine Proteinase Inhibitors)
      0 (Serpins)
      0 (squamous cell carcinoma-related antigen)
      EC 3.4.21.- (Serine Endopeptidases)
    • Publication Date:
      Date Created: 19981113 Date Completed: 19981216 Latest Revision: 20190501
    • Publication Date:
      20250114
    • Accession Number:
      PMC24842
    • Accession Number:
      10.1073/pnas.95.23.13465
    • Accession Number:
      9811823